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Background: Parkinson’s disease is the second most frequent neurodegenerative disorder. Its diagnosis is challenging and mainly relies on clinical aspects. At present, no biomarker is available to obtain a diagnosis of certainty in vivo. Objective: The present review aims at describing machine learning algorithms as they have been variably applied to different aspects of Parkinson’s disease diagnosis and characterization. Methods: A systematic search was conducted on PubMed in December 2019, resulting in 230 publications obtained with the following search query: “Machine Learning” “AND” “Parkinson Disease”. Results: The obtained publications were divided into 6 categories, based on different application fields: “Gait Analysis - Motor Evaluation”, “Upper Limb Motor and Tremor Evaluation”, “Handwriting and typing evaluation”, “Speech and Phonation evaluation”, “Neuroimaging and Nuclear Medicine evaluation”, “Metabolomics application”, after excluding the papers of general topic. As a result, a total of 166 articles were analyzed after elimination of papers written in languages other than English or not directly related to the selected topics. Conclusion: Machine learning algorithms are computer-based statistical approaches that can be trained and are able to find common patterns from big amounts of data. The machine learning approaches can help clinicians in classifying patients according to several variables at the same time.

Background: Viral diseases are responsible for several deaths around the world. Over the past few years, the world has seen several outbreaks caused by viral diseases that, for a long time, seemed to possess no risk. These are diseases that have been forgotten for a long time and, until nowadays, there are no approved drugs or vaccines, leading the pharmaceutical industry and several research groups to run out of time in the search for new pharmacological treatments or prevention methods. In this context, drug repurposing proves to be a fast and economically viable technique, considering the fact that it uses drugs that have a well-established safety profile. Thus, in this review, we present the main advances in drug repurposing and their benefit for searching new treatments against emerging viral diseases. Methods: We conducted a search in the bibliographic databases (Science Direct, Bentham Science, PubMed, Springer, ACS Publisher, Wiley, and NIH’s COVID-19 Portfolio) using the keywords "drug repurposing", "emerging viral infections" and each of the diseases reported here (CoV; ZIKV; DENV; CHIKV; EBOV and MARV) as an inclusion/exclusion criterion. A subjective analysis was performed regarding the quality of the works for inclusion in this manuscript. Thus, the selected works were those that presented drugs repositioned against the emerging viral diseases presented here by means of computational, high-throughput screening or phenotype-based strategies, with no time limit and of relevant scientific value. Results: 291 papers were selected, 24 of which were CHIKV; 52 for ZIKV; 43 for DENV; 35 for EBOV; 10 for MARV; and 56 for CoV and the rest (72 papers) related to the drugs repurposing and emerging viral diseases. Among CoV-related articles, most were published in 2020 (31 papers), updating the current topic. Besides, between the years 2003 - 2005, 10 articles were created, and from 2011 – 2015, there were 7 articles, portraying the outbreaks that occurred at that time. For ZIKV, similar to CoV, most publications were during the period of outbreaks between the years 2016 - 2017 (23 articles). Similarly, most CHIKV (13 papers) and DENV (14 papers) publications occur at the same time interval. For EBOV (13 papers) and MARV (4 papers), they were between the years 2015 - 2016. Through this review, several drugs were highlighted that can be evolved in vivo and clinical trials as possible used against these pathogens showed that remdesivir represent potential treatments against CoV. Furthermore, ribavirin may also be a potential treatment against CHIKV; sofosbuvir against ZIKV; celgosivir against DENV, and favipiravir against EBOV and MARV, representing new hopes against these pathogens. Conclusion: The conclusions of this review manuscript show the potential of the drug repurposing strategy in the discovery of new pharmaceutical products, as from this approach, drugs could be used against emerging viral diseases. Thus, this strategy deserves more attention among research groups and is a promising approach to the discovery of new drugs against emerging viral diseases and also other diseases.

Background: Chronic consumption of alcohol has an adverse effect on the skeletal system, which may lead to osteoporosis, delayed fracture healing and osteonecrosis of the femoral head. Currently, the treatment is limited, therefore, there is an urgent need to determine the underline mechanism and develop a new treatment. It is well-known that normal bone remodeling relies on the balance between osteoclast-mediated bone resorption and - mediated bone formation. Various factors can destroy the balance, including the dysfunction of the immune system. In this review, we summarized the relevant research in the alcoholic osteopenia with a focus on the abnormal osteoimmunology signals. We provided a new theoretical basis for the prevention and treatment of the alcoholic bone. Methods: We searched PubMed for publications from 1 January 1980 to 1 February 2020 to identify relevant and recent literature, summarizing evaluation and the prospect of alcoholic osteopenia. Detailed search terms were ‘alcohol’, ‘alcoholic osteoporosis’, ‘alcoholic osteopenia’ ‘immune’, ‘osteoimmunology’, ‘bone remodeling’, ‘osteoporosis treatment’ and ‘osteoporosis therapy’. Results: A total of 135 papers are included in the review. About 60 papers described the mechanisms of alcohol involved in bone remodeling. Some papers were focused on the pathogenesis of alcohol on bone through osteoimmune mechanisms. Conclusion: There is a complex network of signals between alcohol and bone remodeling and intercellular communication of osteoimmune may be a potential mechanism for alcoholic bone. Studying the osteoimmune mechanism is critical for drug development specific to the alcoholic bone disorder.

Background: Leukotrienes (LTs) constitute a bioactive group of Polyunsaturated Fatty Acid (PUFA) metabolites molded by the enzymatic activity of lipoxygenase (LO) and have a pivotal role in inflammation and allergy. Evidence is accumulating both by in vitro cell culture experiments and animal tumor model studies in support of the direct involvement of aberrant metabolism of arachidonic acid (ACD) in the development of several types of human cancers such as lung, prostate, pancreatic and colorectal malignancies. Several independent experimental data suggest a correlation between tumoral cells viability and LO gene expression, especially, 5-lipoxygenase (5-LO). Overexpressed 5-LO cells live longer, proliferate faster, invade more effectively through extracellular matrix destruction and activate the anti-apoptotic signaling mechanisms more intensively compared to the normal counterparts. Thus, some groups of lipoxygenase inhibitors may be effective as promising chemopreventive agents. Methods: A structured search of bibliographic databases for peer-reviewed research literature regarding the role of LO in the pathogenesis of cancer was performed. The characteristics of screened papers were summarized and the latest advances focused on the discovery of new LO inhibitors as anticancer agents were discussed. Results: More than 180 papers were included and summarized in this review; the majority was about the newly designed and synthesized 5-LO inhibitors as anti-inflammatory and anticancer agents. The enzyme’s structure, 5-LO pathway, 5-LO inhibitors structure-activity relationships as well as the correlation between these drugs and a number of most prevalent human cancers were described. In most cases, it has been emphasized that dual cyclooxygenase-2/5-lipoxygenase (COX-2/5-LO) or dual 5-lipoxygenase/microsomal prostaglandin E synthase-1 (5-LO/mPGES-1) inhibitors possess considerable inhibitory activities against their target enzymes as well as potent antiproliferative effects. Several papers disclosing 5-lipoxygenase activating protein (FLAP) antagonists as a new group of 5-LO activity regulators are also subject to this review. Also, the potential of 12-lipoxygenase (12- LO) and 15-lipoxygenase (15-LO) inhibitors as chemopreventive agents was outlined to expand the scope of new anticancer agents discovery. Some peptides and peptidomimetics with anti-LT activities were described as well. In addition, the cytotoxic effects of lipoxygenase inhibitors and their adverse effects were discussed and some novel series of natural-product-derived inhibitors of LO was also discussed in this review. Conclusion: This review gives insights into the novel lipoxygenase inhibitors with anticancer activity as well as the different molecular pharmacological strategies to inhibit the enzyme effectively. The findings confirm that certain groups of LO inhibitors could act as promising chemopreventive agents.

Despite significant research progress on the pathogenesis, molecular biology, diagnosis,treatment, and prevention of cancer, its morbidity and mortality are still high around theworld. The emerging resistance of cancer cells to anticancer drugs remains still a significantproblem in oncology today. Furthermore, an important challenge is the inability of anticancerdrugs to selectively target tumor cells thus sparing healthy cells.One of the new potential options for efficient and safe therapy can be provided by opioidgrowth factor (OGF), chemically termed Met-enkephalin. It is an endogenous pentapeptide(Tyr-Gly-Gly-Phe-Met) with antitumor, analgesic, and immune-boosting properties. Clinicaltrials have demonstrated that OGF therapy alone, as well as in combination with standardchemotherapies, is a safe, non-toxic anticancer agent that reduces tumor size.In this paper, we review the structure-activity relationship of OGF and its analogues. Wehighlight also OGF derivatives with analgesic, immunomodulatory activity and the ability topenetrate the blood-brain barrier and may be used as safe agents enhancing chemotherapy efficacyand improving quality of life in cancer patients.The reviewed papers indicate that Met-enkephalin and its analogues are interesting candidatesfor the development of novel, non-toxic, and endowed with an analgesic activity anticancerdrugs. More preclinical and clinical studies are needed to explore these opportunities.

Background: Thymoquinone is a promising anticancer molecule, the chemopreventive role of which is well-known at least in vitro and in the animal model. In this review article, we focused on the anti-inflammatory activities of thymoquinone in cancer cells. Method: Research data on inflammation, cancer and thymoquinone were acquired from PubMed, Scopus, Web of Science and Google Scholar. We reviewed papers published since the mid of the last century, and the most cited papers of the last ten years. Results: Studies indicate that thymoquinone possesses immunomodulatory activities, in addition to its chemopreventive role, as thymoquinone can target and modulate inflammatory molecules, like nuclear factor kappa B (NF-Κβ), interleukins, tumor necrosis factor-α (TNF-α), and certain growth factors. As chronic inflammation plays an important role in cancer development, controlling inflammatory pathways is an important mechanism of an anticancer molecule, and modulation of inflammatory pathways might be one of the key mechanisms of thymoquinone’s anticancer activities. Conclusion: This article reviewed the role of inflammation on cancer development, and the action of thymoquinone on inflammatory molecules, which have been proved in vitro and in vivo. Much attention is required for studying the role of thymoquinone in immunotherapeutics and developing this molecule as a future anticancer drug.

Background: Antioxidants are multifaceted molecules playing a crucial role in several cellular functions. There is by now a well-established knowledge about their involvement in numerous processes associated with aging, including vascular damage, neurodegenerative diseases and cancer. An emerging area of application has been lately identified for these compounds in relation to the recent findings indicating their ability to affect biofilm formation by some microbial pathogens, including Staphylococcus aureus, Streptococcus mutans, and Pseudomonas aeruginosa. Methods: A structured search of bibliographic databases for peer-reviewed research literature was performed using a focused review question. The quality of retrieved papers was appraised using standard tools. Results: One hundred sixty-five papers extracted from pubmed database and published in the last fifteen years were included in this review focused on the assessment of the antimicrobial and antibiofilm activity of antioxidant compounds, including vitamins, flavonoids, non-flavonoid polyphenols, and antioxidant polymers. Mechanisms of action of some important antioxidant compounds, especially for vitamin C and phenolic acids, were identified. Conclusions: The findings of this review confirm the potential benefits of the use of natural antioxidants as antimicrobial/antibiofilm compounds. Generally, gram-positive bacteria were found to be more sensitive to antioxidants than gram-negatives. Antioxidant polymeric systems have also been developed mainly derived from functionalization of polysaccharides with antioxidant molecules. The application of such systems in clinics may permit to overcome some issues related to the systemic delivery of antioxidants, such as poor absorption, loss of bioactivity, and limited half-life. However, investigations focused on the study of antibiofilm activity of antioxidant polymers are still very limited in number and therefore they are strongly encouraged in order to lay the foundations for application of antioxidant polymers in treatment of biofilm-based infections.

Recent trends in research and investigation on nanoemulsion based products is the result of many reasons such as food security as a global concern, increasing demand for highly efficient food and agricultural products and technological need for products with the ability of manipulation and optimization in their properties. Nanoemulsions are defined as emulsions made up of nano sized droplets dispersed in another immiscible liquid which exhibit properties distinguishing them from conventional emulsions and making them suitable for encapsulation, delivery and formulations of bioactive ingredients in different fields including drugs, food and agriculture. The objective of this paper is to present a general overview of nanoemulsions definition, their preparation methods, properties and applications in food and agricultural sectors. Due to physicochemical properties of the nanoemulsion composition, creating nanosized droplets requires high/low energy methods that can be supplied by special devices or techniques. An overview about the mechanisms of these methods is also presented in this paper which are commonly used to prepare nanoemulsions. Finally, some recent works about the application of nanoemulsions in food and agricultural sectors along with challenges and legislations restricting their applications is discussed in the last sections of the current study.

Background: This paper provides a critical review of biopolymer-based substrates, especially the cellulose derivatives, for their application in buccal drug delivery. Drug delivery to the buccal mucous has the benefits of immobile muscle, abundant vascularization and rapid recovery, but not all the drugs can be administered through the buccal mucosa (e.g., macromolecular drugs), due to the low bioavailability caused by their large molecular size. This shortfall inspired the rapid development of drug-compounding technologies and the corresponding usage of biopolymer substrates. Methods: Cellulose derivatives have been extensively developed for drug manufacturing to facilitate its delivery. We engaged in structured research of cellulose-based drug compounding technologies. We summarized the characteristic cellulose derivatives which have been used as the biocompatible substrates in buccal delivery systems. The discussion of potential use of the rapidly-developed nanocellulose (NC) is also notable in this paper. Results: Seventy-eight papers were referenced in this perspective paper with the majority (sixty-five) published later than 2010. Forty-seven papers defined the buccal drug delivery systems and their substrates. Fifteen papers outlined the properties and applications of cellulose derivatives. Nanocellulose was introduced as a leading edge of nanomaterial with sixteen papers highlighted its adaptability in drug compounding for buccal delivery. Conclusion: The findings of this perspective paper proposed the potential use of cellulose derivatives, the typical kind of biopolymers, in the buccal drug delivery system for promoting the bioavailability of macromolecular drugs. Nanocellulose (NC) in particular was proposed as an innovative bio-binder/carrier for the controlled-release of drugs in buccal system.

Background: Intercellular crosstalk among osteoblast, osteoclast, osteocyte and chondrocyte is involved in the precise control of bone homeostasis. Disruption of this cellular and molecular signaling would lead to metabolic bone diseases such as osteoporosis. Currently a number of anti-osteoporosis interventions are restricted by side effects, complications and long-term intolerance. This review aims to summarize the bone cellular communication involved in bone remodeling and its usage to develop new drugs for osteoporosis. Methods: We searched PubMed for publications from 1 January 1980 to 1 January 2018 to identify relevant and latest literatures, evaluation and prospect of osteoporosis medication were summarized. Detailed search terms were ‘osteoporosis’, ‘osteocyte’, ‘osteoblast’, ‘osteoclast’, ‘bone remodeling’, ‘chondrocyte’, ‘osteoporosis treatment’, ‘osteoporosis therapy’, ‘bisphosphonates’, ‘denosumab’, ‘Selective Estrogen Receptor Modulator (SERM)’, ‘PTH’, ‘romosozumab’, ‘dkk-1 antagonist’, ‘strontium ranelate’. Results: A total of 170 papers were included in the review. About 80 papers described bone cell interactions involved in bone remodeling. The remaining papers were focused on the novel advanced and new horizons in osteoporosis therapies. Conclusion: There exists a complex signal network among bone cells involved in bone remodeling. The disorder of cell-cell communications may be the underlying mechanism of osteoporosis. Current anti-osteoporosis therapies are effective but accompanied by certain drawbacks simultaneously. Restoring the abnormal signal network and individualized therapy are critical for ideal drug development.

Background: Tuberculosis (TB) has been present in the history of human civilization since time immemorial and has caused more deaths than any other infectious disease. It is still considered one of the ten most common epidemiologic causes of death in the world. As a transmissible disease, it is initiated by rod-shaped (bacillus) mycobacteria. The management of tuberculosis became possible owing to several discoveries beginning in 1882 with the isolation of the TB bacillus by Robert Koch. The diagnosis of TB was enabled by finding a staining method for TB bacteria identification (1883). It was soon realized that a large-scale policy for the treatment and prevention of tuberculosis was necessary, which resulted in the foundation of International Union against Tuberculosis and Lung Diseases (1902). An antituberculosis vaccine was developed in 1921 and has been in therapeutic use since then. TB treatment regimens have changed over the decades and the latest recommendations are known as Directly Observed Treatment Short-course (DOTS, WHO 1993). Methods: A search of bibliographic databases was performed for peer-reviewed research literature. A focused review question and inclusion criteria were applied. Standard tools were used to assess the quality of retrieved papers. Results: A total of 112 papers were included comprising original publications and reviews. The paper overviews anti-TB drugs according to their mechanism of action. The chemical structure, metabolism and unwanted effects of such drugs have been discussed. The most recent treatment regimens and new drugs, including those in clinical trials, are also presented. Conclusion: Despite a 22% decrease in the tuberculosis fatality rate observed between 2000 and 2015, the disease remains one of the ten prime causes of death worldwide. Increasing bacterial resistance and expensive, prolonged therapies are the main reasons for efforts to find effective drugs or antituberculosis regimens, especially to cure multidrug-resistant tuberculosis.

Background: Obesity is now recognized as a worldwide health issue and has reached epidemic proportions, affecting both developed and developing countries. The World Obesity Federation stated that “Obesity is a chronic relapsing disease process”: as a result, obesity has been recognized internationally as a chronic disease. The primary cause of the metabolic syndrome and increase of the cardiovascular risk have been identified in "sick fat", a condition then defined as adiposopathy. Heart attacks, strokes and renal failures are pathologies that have mid-risk factors such as dyslipidemia, hypertension and diabetes, which in turn are caused by obesity, whose primary risk factor is represented by the diet. The aim of the present review is to consider the importance of body composition, together with chronic inflammation and a new gut microbiota data that may turn out to be crucial elements of some target treatment of human obesity. Methods: In this review, we performed research using PubMed database reviewing the evidence in the literature of evidence information regarding the link between obesity and body composition in the development of metabolic disease via inflammation markers and in particular, the new role exerted by gut microbiota. Results: Several papers were evaluated searching for differences in fat mass and disease risk. We also identified the same papers dealing with differences in body composition and metabolic syndrome. Our attention focuses also on a new frontier of gut microbiota composition in the body weight decrease and anti-inflammatory effects. Conclusion: To the saving of lean mass, for the prevention of cardiometabolic diseases, also considering the relationship with obesity, it is necessary to reduce the inflammatory state, acting on the gut-microbiota and on the intestinal permeability. To improve the health of the intestinal flora, we propose a 4P medicine and treatment with probiotics, prebiotics, postbiotics, and polyphenols.

Background: Synthetic compounds with pharmaceutical applications in brain disorders are daily designed and synthesized, with well first effects but also seldom severe side effects. This imposes the search for alternative therapies based on the pharmaceutical potentials of natural compounds. The natural compounds isolated from various plants and arthropods venom are well known for their antimicrobial (antibacterial, antiviral) and antiinflammatory activities, but more studies are needed for a better understanding of their structural and pharmacological features with new therapeutic applications. Objectives: Here we present some structural and pharmaceutical features of natural compounds isolated from plants and arthropods venom relevant for their efficiency and potency in brain disorders. We present the polytherapeutic effects of natural compounds belonging to terpenes (limonene), monoterpenoids (1,8-cineole) and stilbenes (resveratrol), as well as natural peptides (apamin, mastoparan and melittin). Methods: Various experimental and in silico methods are presented with special attention on bioinformatics (natural compounds database, artificial neural network) and cheminformatics (QSAR, drug design, computational mutagenesis, molecular docking). Results: In the present paper we reviewed: (i) recent studies regarding the pharmacological potential of natural compounds in the brain; (ii) the most useful databases containing molecular and functional features of natural compounds; and (iii) the most important molecular descriptors of natural compounds in comparison with a few synthetic compounds. Conclusion: Our paper indicates that natural compounds are a real alternative for nervous system therapy and represents a helpful tool for the future papers focused on the study of the natural compounds.

Background: The rapidly increasing number of known protein sequences calls for more efficient methods to predict the Three-Dimensional (3D) structures of proteins, thus providing basic knowledge for rational drug design. Understanding the folding mechanism of proteins is valuable for predicting their 3D structures and for designing proteins with new functions and medicinal applications. Levinthal’s paradox is that although the astronomical number of conformations possible even for proteins as small as 100 residues cannot be fully sampled, proteins in nature normally fold into the native state within timescales ranging from microseconds to hours. These conflicting results reveal that there are factors in organisms that can assist in protein folding. Methods: In this paper, we selected a crowded cell-like environment and temperature, and the top three Posttranslational Modifications (PTMs) as examples to show that Levinthal’s paradox does not reflect the folding mechanism of proteins. We then revealed the effects of these factors on protein folding. Results: The results summarized in this review indicate that a crowded cell-like environment, temperature, and the top three PTMs reshape the Free Energy Landscapes (FELs) of proteins, thereby regulating the folding process. The balance between entropy and enthalpy is the key to understanding the effect of the crowded cell-like environment and PTMs on protein folding. In addition, the stability/flexibility of proteins is regulated by temperature. Conclusion: This paper concludes that the cellular environment could directly intervene in protein folding. The long-term interactions of the cellular environment and sequence evolution may enable proteins to fold efficiently. Therefore, to correctly understand the folding mechanism of proteins, the effect of the cellular environment on protein folding should be considered.

Background: Dual-targeting in cancer treatment by a single drug is an unconventional approach in relation to drug combinations. The rationale for the development of dualtargeting agents is to overcome incomplete efficacy and drug resistance frequently present when applying individual targeting agents. Consequently, -a more favorable outcome of cancer treatment is expected with dual-targeting strategies. Methods: We reviewed the literature, concentrating on the association between clinically relevant and/or novel dual inhibitors with the potential to modulate multidrug resistant phenotype of cancer cells, particularly the activity of P-glycoprotein. A balanced analysis of content was performed to emphasize the most important findings and optimize the structure of this review. Results: Two-hundred and forty-five papers were included in the review. The introductory part was interpreted by 9 papers. Tyrosine kinase inhibitors’ role in the inhibition of Pglycoprotein and chemosensitization was illustrated by 87 papers. The contribution of naturalbased compounds in overcoming multidrug resistance was reviewed using 92 papers, while specific dual inhibitors acting against microtubule assembling and/or topoisomerases were described with 55 papers. Eleven papers gave an insight into a novel and less explored approach with hybrid drugs. Their influence on P-glycoprotein and multidrug resistance was also evaluated. Conclusion: These findings bring into focus rational anticancer strategies with dual-targeting agents. Most evaluated synthetic and natural drugs showed a great potential in chemosensitization. Further steps in this direction are needed for the optimization of anticancer treatment.

Background: Porous micro- and nanoparticles have the capacity to encapsulate a large quantity of therapeutics, making them promising delivery vehicles for a variety of applications. This review aims to highlight the latest development of inorganic and hybrid (inorganic/ organic) particles for drug delivery with an additional emphasis on combatting drug resistant cancer. We go one step further and discuss delivery applications beyond medicinal delivery, as there is generally a translation from medicinal delivery to botanic delivery after a short lag time. Methods: We undertook a search of relevant peer-reviewed publications. The quality of the relevant papers was appraised using standard tools. The characteristics of the papers are described herein, and the relevant material and therapeutic properties are discussed. Results: We discuss 4 classes of porous particles in terms of drug delivery and theranostics. We specifically focus on silica, calcium carbonate, metal-phenolic network, and metalorganic framework particles. Other relevant biomedically relevant applications are discussed and we highlight outstanding therapeutic results in the relevant literature. Conclusion: The findings of this review confirm the importance of studying and utilizing porous particles for therapeutic delivery. Moreover, we show that the properties of porous particles that make them promising for medicinal drug delivery also make them promising candidates for agro-industrial applications.

Background: The possibilities of treatment for oncological diseases are growing enormously in the last decades. Unfortunately, these developments have led to the onset of resistances with regards to the new treatments. This is particularly true if we face with the therapeutic field of Tyrosine Kinase Inhibitors (TKIs). This review gives an overview of possible TKI resistances that can occur during the treatment of an oncologic diesease and available strategies that can be adopted, taking cues from a successful example such as CML. Methods: We performed a literature search for peer-reviewed articles using different databases, such as PubMed and Scopus, and exploiting different keywords and different logical operators. Results: 68 papers were included in the review. Twenty-four papers give an overview of the causes of TKIs resistances in the wide oncologic field. The remaining papers deal CML, deeply analysing the TKIs Resistances present in this pathology and the strategies adopted to overcome them. Conclusion: The aim of this review is to furnish an overview and a methodological guideline for the approach and the overcoming of TKIs Resistances.

Background: As a new kind of green media and bioactive compounds with special structure, Ionic Liquids (ILs) are attracting much attention and applied widely in many fields. However, their roles and potential have not been fully recognized by many researchers of medicinal chemistry. Because of obvious differences from other traditional drugs and reagents, their uses and performance together with advantages and disadvantages need to be explored and reviewed in detail. Methods: For a systematic and explicit description of the relationship between ILs and medicinal chemistry, all of the contents were elucidated and summarized in a series of independent parts. In each part, it started from the research background or a conceptual framework and then specific examples were introduced to illustrate the theme. Finally, the important conclusions were drawn and its future was outlooked after the discussion about related key problems appearing in each mentioned research. Meanwhile, methodologies such as empirical analysis, comparison and induction were applied in different sections to exposit our subject. Results: The whole review was composed of five parts, and 148 papers were cited in total. Related basic information of ionic liquids was provided on the basis of representative references, including their concepts and important characters. Then 82 papers outlined ionic liquid-like active pharmaceutical ingredients, which unfolded with their major biological activities (antimicrobial activity, antibiofilm activity, antitumor activity, anticholinesterase activity and so on). Applications of ionic liquids in the synthesis of drugs and pharmaceutical intermediates were elaborated in 92 papers to illustrate the important roles of ILs and their extraordinary properties in this field. Moreover, new technologies (such as immobilization of IL, microwave reaction, solventfree synthesis, microreactor, etc) were introduced for further innovation. Finally, 26 papers were included to expound the status of the IL-assisted derivatization of various natural lead compounds. Conclusion: This review placed emphasis on chemical structures of ILs and their structureactivity relationships in a specific manner, leading to meaningful and valuable related information to some related fields and thus promotes further development and application of various ILs for medicinal chemistry. The deep exploration for key scientific problems is the driving force to propel their theoretical breakthrough and industrial production.

Background: Due to the non-toxicity, abundance and biodegradability, recently more and more attention has been focused on the exploration of hemicellulose as the potential substrate for the production of liquid fuels and other value-added chemicals and materials in different fields. This review aims to summarize the current knowledge on the promising application of nature hemicellulose and its derivative products including its degradation products, its new derivatives and hemicellulosebased medical biodegradable materials in the medical and pharmaceutical field, especially for inmmune regulation, bacteria inhibition, drug release, anti-caries, scaffold materials and anti-tumor. Methods: We searched the related papers about the medical and pharmaceutical application of hemicellulose and its derivative products, and summarized their preparation methods, properties and use effects. Results: Two hundred and twenty-seven papers were included in this review. Forty-seven papers introduced the extraction and application in immune regulation of nature hemicellulose, such as xylan, mannan, xyloglucan (XG) and β-glucan. Seventy-seven papers mentioned the preparation and application of degradation products of hemicellulose for adjusting intestinal function, maintaining blood glucose levels, enhancing the immunity and alleviating human fatigue fields such as xylooligosaccharides, xylitol, xylose, arabinose, etc. The preparation of hemicellulose derivatives were described in thirty-two papers such as hemicellulose esters, hemicellulose ethers and their effects on anticoagulants, adsorption of creatinine, the addition of immune cells and the inhibition of harmful bacteria. Finally, the preparations of hemicellulose-based materials such as hydrogels and membrane for the field of drug release, cell immobilization, cancer therapy and wound dressings were presented using fifty-five papers. Conclusion: The structure of hemicellulose-based products has the significant impact on properties and the use effect for the immunity, and treating various diseases of human. However, some efforts should be made to explore and improve the properties of hemicellulose-based products and design the new materials to broaden hemicellulose applications.

Background: Elucidating the mechanisms of recurrence of embryonic signaling pathways in tumorigenesis has led to the discovery of onco-fetal players which have physiological roles during normal development but result aberrantly re-activated in tumors. In this context, Nodal and Cripto-1 are recognized as onco-developmental factors, which are absent in normal tissues but are overexpressed in several solid tumors where they can serve as theranostic agents. Objective: To collect, review and discuss the most relevant papers related to the involvement of Nodal and Cripto-1 in the development, progression, recurrence and metastasis of several tumors where they are over-expressed, with a particular attention to their occurrence on the surface of the corresponding sub-populations of cancer stem cells (CSC). Results: We have gathered, rationalized and discussed the most interesting findings extracted from some 370 papers related to the involvement of Cripto-1 and Nodal in all tumor types where they have been detected. Data demonstrate the clear connection between Nodal and Cripto-1 presence and their multiple oncogenic activities across different tumors. We have also reviewed and highlighted the potential of targeting Nodal, Cripto-1 and the complexes that they form on the surface of tumor cells, especially of CSC, as an innovative approach to detect and suppress tumors with molecules that block one or more mechanisms that they regulate. Conclusion: Overall, Nodal and Cripto-1 represent two innovative and effective biomarkers for developing potential theranostic anti-tumor agents that target normal as well as CSC subpopulations and overcome both pharmacological resistance and tumor relapse.

Background: Irinotecan (IRI) is a widely used chemotherapeutic drug, mostly used for first-line treatment of colorectal and pancreatic cancer. IRI doses are usually established based on patient’s body surface area, an approach associated with large inter-individual variability in drug exposure and high incidence of severe toxicity. Toxic and therapeutic effects of IRI are also due to its active metabolite SN-38, reported to be up to 100 times more cytotoxic than IRI. SN-38 is detoxified by the formation of SN-38 glucuronide, through UGT1A1. Genetic polymorphisms in the UGT1A1 gene are associated to higher exposures to SN-38 and severe toxicity. Pharmacokinetic models to describe IRI and SN-38 kinetic profiles are available, with few studies exploring pharmacokinetic and pharmacogenetic-based dose individualization. The aim of this manuscript is to review the available evidence supporting pharmacogenetic and pharmacokinetic dose individualization of IRI in order to reduce the occurrence of severe toxicity during cancer treatment. Methods: The PubMed database was searched, considering papers published in the period from 1995-2017, using the keywords irinotecan, pharmacogenetics, metabolic genotyping, dose individualization, therapeutic drug monitoring, pharmacokinetics and pharmacodynamics, either alone or in combination, with original papers being selected based on the presence of relevant data. Conclusion: The findings of this review confirm the importance of considering individual patient characteristics to select IRI doses. Currently, the most straightforward approach for IRI dose individualization is UGT1A1 genotyping. However, this strategy is sub-optimal due to several other genetic and environmental contributions to the variable pharmacokinetics of IRI and its active metabolite. The use of dried blood spot sampling could allow the clinical application of limited sampling and population pharmacokinetic models for IRI doses individualization.

Background: Application of coordination chemistry in nanotechnology is a rapidly developing research field in medicine. Bismuth complexes have been widely used in biomedicine with satisfactory therapeutic effects, mostly in Helicobacter pylori eradication, but also as potential antimicrobial and anti-leishmanial agents. Additionally, in recent years, application of bismuth-based compounds as potent anticancer drugs has been studied extensively. Methods: Search for data connected with recent trends on bismuth compounds in cancer chemo- and radiotherapy was carried out using web-based literature searching tools such as ScienceDirect, Springer, Royal Society of Chemistry, American Chemical Society and Wiley. Pertinent literature is covered up to 2016. Results: In this review, based on 213 papers, we highlighted a number of current problems connected with: (i) characterization of bismuth complexes with selected thiosemicarbazone, hydrazone, and dithiocarbamate classes of ligands as potential chemotherapeutics. Literature results derived from 50 papers show that almost all bismuth compounds inhibit growth and proliferation of breast, colon, ovarian, lung, and other tumours; (ii) pioneering research on application of bismuth-based nanoparticles and nanodots for radiosensitization. Results show great promise for improvement in therapeutic efficacy of ionizing radiation in advanced radiotherapy (described in 36 papers); and (iii) research challenges in using bismuth radionuclides in targeted radioimmunotherapy, connected with choice of adequate radionuclide, targeting vector, proper bifunctional ligand and problems with 213Bi recoil daughters toxicity (derived from 92 papers). Conclusion: This review presents recent research trends on bismuth compounds in cancer chemo- and radiotherapy, suggesting directions for future research.

Background: ATP-binding cassette (ABC) transporters-mediated multidrug resistance (MDR) remains the major obstacle for effective cancer therapy. Nanoparticles (NPs)-based delivery systems are promising to overcome MDR, but only a few of them have been accepted for clinical treatment, which should be due to their insufficient transportation and potential toxicity. In this respect, more and more attentions are being attracted on the interactions between NPs and ABC transporters, which hold a key role in the treatment of MDR cancer and the toxicity of NPs. However, there are no systematic reviews about such interactions, especially about their corresponding mechanism. Methods: We undertook extensive search of PubMed databases for peer-reviewed literatures using focused review questions. The retrieved papers were mostly published within the 5 years (84 of 104) and all with an impact factor above 2. First, this review focused on the current knowledge of ABC transporters involved in MDR and their inhibitors. Then, we reviewed the most recent literature about the inhibitory effects of organic NPs' excipients on ABC transporters and the direct interactions of inorganic NPs with ABC transporters. The major elements of obtained papers were described and classified depending on the structure of NPs. Results: Both organic and inorganic NPs can inhibit the function of ABC transporters, but based on different mechanisms. The effects of organic NPs are caused by several excipients like surfactants, polymers, lipids and cyclodextrin. Meanwhile, inorganic NPs usually act as the substrates of ABC transporters and competitively inhibit the efflux of drugs. These phenomena are interesting and worth investigating. Conclusion: The finding of this review confirmed the potential interactions between NPs and ABC transporters. These phenomena are interesting and worth investigating, and a knowledge of related mechanism would not only be important for the clinical therapies toward overcoming cancer MDR, but also help the treatment of other diseases like tuberculosis, AIDS, and central nervous system disorders, whose drugresistance was also related to ABC transporter-mediated efflux.

Background: Polymers have wide applications in medicine, including dentistry, i.e. in prosthetic dentistry. Aim: The following paper is aimed at demonstrating the applications of selected modern polymers in prosthetic dentistry based on the reported literature. Material and Methods: The study was conducted using the PubMed, SCOPUS and CINAHL databases in relation to documents published during 1999–2017. The following keywords were used: polymers with prosthetic dentistry, impression materials, denture base materials, bite registration materials, denture soft liners, occlusal splint materials and 3D printing. Original papers and reviews which were significant from the modern clinical viewpoint and practical validity in relation to the possibility of using polymeric materials in prosthetic dentistry were presented. Results: Denture base materials were the most commonly modified polymers. Modifications mainly concerned antimicrobial properties and reinforcement of the material structure by introducing additional fibers. Antimicrobial modifications were also common in case of relining materials. Conclusion: Polymeric materials have widely been used in prosthetic dentistry. Modifications of their composition allow achieving new, beneficial properties that affect the quality of patients' life. Progress in science allows for a more methodologically-advanced research on the synthesis of new polymeric materials and incorporation of new substances into already known polymeric materials, that will require systematization and appropriate classification.

Background: Recent years have brought the dynamic development in studies of naphthoquinones obtained from plants, in vitro cultures and semi- or total synthesis. This review presents the hairy root cultures approach for producing naphthoquinones and summarizes their most recent anti-cancer investigations. Objective: This review aimed to define biotechnological strategies impacted on naphthoquinones production in hairy root cultures. Up to now the major source of shikonin/alkannin derivatives, rhinacanthins and ramentaceone is isolation from plant material, also derived via biotechnological methods. Moreover, the most recent anti-cancer activity studies on naphthoquinones which could be produced in hairy root cultures were outlined. Methods: For databases survey two selection criteria were used: (i) naphthoquinone could be produced in hairy roots, and (ii) it exhibits anti-cancer properties. Results: Ninety two papers were included in the review, thirty described biotechnological approaches enhancing naphthoquinones production, among them twenty seven were dedicated to hairy root cultures. Forty papers outlined the anti-cancer activity of targeted naphthoquinones including the type of cancer and bioassays description. The synergistic effect of natural naphthoquinones and other anti-cancer therapies was reviewed and toxicity of natural naphthoquinones and plant extracts was discussed. The review highlights tendencies in hairy root investigations and indicates the possible future research directions for improving biotechnological production efficacy. Conclusion: This review demonstrates a great potential of hairy root cultures for naphthoquinones production, which could be furtherly developed for future medical purposes, especially as anti-cancer agents. This area of plant biotechnology will be surely still developed with traditional and new strategies.

Background: The Mediterranean basin is one of the richest biodiversity areas in the world, and the use of medicinal plants for treating cancer in this area has been documented for generations in different cultures. Objective: To present and discuss the findings related to medicinal plants with confirmed data on active compounds and/or clear mode of action. Methods: We undertook a structured search of bibliography of peer-reviewed research literature using key words and a focused review question. Papers with sufficient quality were reviewed, their findings presented and integrated into a coherent, state of the art document on wild plants of the Middle East with anti-cancer activity. Results: 121 papers were included in the review, among them 10 define herbal medicine, 3 describe the status of cancer worldwide, 18 discuss biodiversity, chemodiversity, ethnopharmacological survey and conservation of medicinal plants, 12 describe well known natural products from plants used to treat cancer and 78 papers describe specific compounds and mode of action in different wild plants from the middle east, traditionally used to treat cancer. Conclusions: Confirmed data on active compounds and/or clear mode of action exist for several wild plants traditionally used in herbal medicine to treat cancer. Yet, medicinal plants were mainly gathered from the wild, resulting in some of the commonly used herbs becoming endangered species. Also, in many cases, the activity and biochemical profile of plants harvested over different time spans and ecosystems may vary. Rational cultivation may ensure optimized yield with a uniform high quality of products.

Background: Chronic pain states are clinically relevant and yet unsolved conditions impacting on quality of life and representing an important social and economic burden; these diseases are poorly treated with the currently available drugs, being urgent the need of innovative analgesics. In this frame, novel analogues of endomorphin-1 and dermorphin emerge as promising starting points to develop innovative, more effective analgesics to treat neuropathic pain. Methods: An extensive and structured search of bibliographic databases for peer-reviewed research literature was undertaken using focused review questions; all the retrieved papers were published on prestigious international journals by the experts of the field and were carefully analyzed to collect all the information and data necessary to the conceptual framework of this review. Results: One hundred papers were included in this review; forty-one defined the up-to-date findings on neuropathic pain etiopathogenesis and its currently available treatment options. Thirty-five papers described all the advantages and drawbacks of using endomorphin-1 (23) or dermorphin (12) in the frame of neuropathic pain and outlined the most relevant advances in developing endomorphin-1 and dermorphin analogs useful as potential, innovative analgesics. Twenty-four papers provided the latest insights into exploiting biased agonism at opioid receptor as an innovative strategy to develop more effective and safer analgesics. Conclusion: This review reports that innovative opioid peptides will be of great help in better understanding the multifaceted scenario of neuropathic pain treatment, providing very interesting opportunities for the identification of novel and more effective opioid analgesics to be employed as medications.

Background: Diabetes mellitus type 2 (DMT2) is an endocrine disease of global proportions which is currently affecting 1 in 12 adults in the world, with still increasing prevalence. World Health Organization (WHO) declared this worldwide health problem, as an epidemic disease, to be the only non-infectious disease with such categorization. People with DMT2 are at increased risk of various complications and have shorter life expectancy. The main classes of oral antidiabetic drugs accessible today for DMT2 vary in their chemical composition, modes of action, safety profiles and tolerability. Methods: A systematic search of peer-reviewed scientific literature and public databases has been conducted. We included the most recent relevant research papers and data in respect to the focus of the present review. The quality of retrieved papers was assessed using standard tools. Results: The review highlights the chemical structural diversity of the molecules that have the common target-DMT2. So-called traditional antidiabetics as well as the newest and the least explored drugs include polypeptides and amino acid derivatives (insulin, glucagon-like peptide 1, dipeptidyl peptidase-IV inhibitors, amylin), sulfonylurea derivatives, benzylthiazolidine- 2,4-diones (peroxisome proliferator activated receptor-γ agonists/glitazones), condensed guanido core (metformin) and sugar-like molecules (α-glucosidase and sodium/ glucose co-transporter 2 inhibitors). Conclusion: As diabetes becomes a more common disease, interest in new pharmacological targets is on the rise.

Background: Chronic kidney disease (CKD) remains a major challenge for Public Health systems and corresponds to the replacement of renal functional tissue by extra-cellular matrix proteins such as collagens and fibronectin. There is no efficient treatment to date for CKD except nephroprotective strategies. The cannabinoid system and more specifically the cannabinoid receptors 1 (CB1) and 2 (CB2) may represent a new therapeutic target in CKD. Methods: We performed PubMed searches using the terms “cannabinoid receptors” in combination with “kidney” or “renal disease” or “nephropathy” or “diabetes” or “renal fibrosis” or “cellular pathways” in various combinations. We analyzed full-text English-language papers. We also searched the reference lists of identified articles for further relevant papers. Results: We gathered data regarding the current state of knowledge on the cannabinoid system in normal renal physiology and in various experimental nephropathies, especially diabetes. We also reviewed data obtained in models of diabetes and obesity as well as in non metabolic models of renal fibrosis when CB1 blockers and/or CB2 agonists were used. We also found that very few data are available so far regarding the cellular pathways involved downstream of the cannabinoid receptors in the development of renal fibrosis. Conclusion: Overall, we found that the cannabinoid receptors are a promising target in the development of renal disease and fibrosis, particularly in CKD and diabetes.

Background: Considerable evidence demonstrates the importance of dithiocarbamates especially disulfiram as anticancer drugs. However there are no systematic reviews outlining how their metal-binding ability is related to their anticancer activity. This review aims to summarize chemical features and metal-binding activity of disulfiram and its metabolite DEDTC, and discuss different mechanisms of action of disulfiram and their contributions to the drug's anticancer activity. Methods: We undertook a disulfiram-related search on bibliographic databases of peerreviewed research literature, including many historic papers and in vitro, in vivo, preclinical and clinical studies. The selected papers were carefully reviewed and summarized. Results: More than five hundreds of papers were obtained in the initial search and one hundred eighteen (118) papers were included in the review, most of which deal with chemical and biological aspects of Disulfiram and the relationship of its chemical and biological properties. Eighty one (81) papers outline biological aspects of dithiocarbamates, and fifty seven (57) papers report biological activity of Disulfiram as an inhibitor of proteasomes or inhibitor of aldehyde dehydrogenase enzymes, interaction with other anticancer drugs, or mechanism of action related to reactive oxygen species. Other papers reviewed focus on chemical aspects of dithiocarbamates. Conclusion: This review confirms the importance of chemical features of compounds such as Disulfiram to their biological activities, and supports repurposing DSF as a potential anticancer agent.

Background: The inherent problems accompanying chemotherapy necessitate the development of new anticancer approaches. The development of compounds that can disrupt cancerous cellular machinery by novel mechanisms, via interactions with proteins and non-canonical DNA structures (e.g. G-quadruplexes), as well as by alteration of the intracellular redox balance, is nowadays focus of intense research. In this context, organometallic compounds of the noble metals Pt and Au have become prominent experimental therapeutic agents. This review provides an overview of the Pt(II) and Au(III) cyclometalated compounds with a chelating ring containing a strong C-M σ -bond to improve the stability of the compounds with respect to ligand exchange reactions and biological reduction. Furthermore, these properties can be easily tuned by modification of either the anionic cyclometalated or the ancillary ligands. Special focus has been set to C^N, C^N^C, C^N^N and C^N^S platinum(II) and gold(III) pincer complexes regarding their synthesis and biological mechanisms of action as anticancer agents. Methods: A structured search of both chemical and medicinal databases for peerreviewed research literature has been conducted. The quality of retrieved papers was appraised using standard tools. The synthesis as well as the chemical and biological properties of the described compounds were carefully reviewed and described. The findings were outlined using a conceptual framework. Results: In this review we included 155 papers, the majority originating from high-impact papers on the synthesis and biological modes of platinum(II) and gold(III) compounds. Among them, 17 papers were highlighted to give an introduction to the use of Pt and Au compounds with medicinal properties, mainly focussing on coordination compounds. The synthesis and medicinal properties of organometallic compounds of various metals (such as Fe, Ru, Ti) were outlined in 51 papers. These compounds included metallocenes, metallo- arenes, metallo-carbonyls, metallo-carbenes (e.g. N-heterocyclic carbenes), and alkynyl complexes. The C^N, C^N^C, C^N^N and C^N^S pincer complexes of platinum( II) (46 papers) and gold(III) (44 papers) were discussed concerning their synthesis, stability and advantages to develop therapeutic compounds. We strove to show the consistent development of C^N, C^N^C, C^N^N and C^N^S platinum(II) and gold(III) pincer complexes regarding their synthesis and biological modes from the early beginnings to the most recent findings. Conclusion: This review supplies a profound overview of the development of organometallic compounds for medicinal purposes, setting special focus to the synthesis and stability of C^N, C^N^C, C^N^N and C^N^S pincer complexes of platinum(II) and gold(III) and their use as anticancer agents.

Background: Fungi play an important role in terrestrial ecosystems interacting positively or negatively with plants. These interactions are complex and the outcomes are different depending on the fungal lifestyles, saprotrophic, mutualistic or pathogenic. Furthermore, fungi are well known for producing secondary metabolites, originating from different biosynthetic pathways, which possess biological properties of considerable biotechnological interest. Among the terrestrial ecosystems, temperate forests represent an enormous reservoir of fungal diversity. This review will highlight the goldmine of secondary metabolites produced by pathogenic and endophytic fungi of forest trees with focus on their biological activities. Methods: A structured search of bibliographic databases for peer-reviewed research literature was undertaken using a research discovery application providing access to a large and authoritative source of references. The papers selected were examined and the main results were reported and discussed. Results: Two hundred forthy-one papers were included in the review, outlined a large number of secondary metabolites produced by pathogenic and endophiltic fungi and their biological activities, including phytotoxic, antifungal, antioomycetes, antibacterial, brine shrimp lethality, mosquito biting deterrence and larvicidal, cytotoxic, antiproliferative and many other bioactivities. Conclusion: The findings of this review confirm the importance of secondary metabolites produced by pathogenic and endophytic fungi from forest plants growing in temperate regions as an excellent prospects to discover compounds with new bioactivities and mode of actions. In addition, the potential of some metabolites as a source of new drugs and biopesticides is underlined.

Background: Gold nanoparticles (AuNPs), owing to their elegant physicochemical properties, have recently been introduced as promising theranostic nanoparticles. Folic acid is a necessary vitamin for cell proliferation. Accordingly, the surface functionalization of AuNP with folic acid may offer a great potential for the development of a strategy to increase the efficiency of cancer diagnosis and therapy based on the new nanotechnology. In this study, we have reviewed the recent progress made in the design and the biomedical application of various folate-conjugated gold nanoparticles (FAuNPs). Methods: We performed a structured search in bibliographic databases and made a comprehensive list of relevant papers. The main subjects considered in this review included (1) methods for the preparation of F-AuNPs, (2) applications of F-AuNPs in computed tomography (CT), and (3) the use of F-AuNPs in targeted cancer therapy. Results: As many as 96 papers were selected for the review. Accordingly, we explained the noncovalent and the covalent methods of fabricating the various types of F-AuNPs. Particular applications of F-AuNP in cancer diagnosis using the CT scan modality were described. In addition, the applications of F-AuNPs in targeted radiation therapy, chemotherapy, and hyperthermia were elucidated in depth. In the hyperthermia section, we presented certain extra explanations on F-AuNP-based laser, radiofrequency, and ultrasoundbased hyperthermia methods. Conclusion: This review identifies the important roles of F-AuNPs in current cancer studies that are being undertaken worldwide. The findings of this review confirm that F-AuNP is a new theranostic agent, which has a great potential for simultaneous cancer therapy and diagnosis.

Background: The complex architecture of the mycobacterial cell wall is responsible for many physiological and infection-associated properties of these pathogens. Long chain mycolic acids with chiral functional groups constitute a major lipid envelope component, and therefore play a crucial role in determining the permeability and fluidity of the cell wall. Varying proportions of the different mycolate types are present in various mycobacteria. This serves to designate a specific mycolic acid profile, allowing the differentiation of species and subspecies. Objective: In this review, we explore the diversity in mycolic acid chemical structure, its influence on cell wall permeability and consequences for virulence, and present how they might be exploited as research targets in diagnosis and chemotherapy. Methods: The search of bibliographic databases for adequate, informative and valuable peerreviewed literature was undertaken. The proper papers were identified by the hand and electronic searching through the relevant to the topic-leading journals, key words, named authors, reference scanning, etc. Results: The review is based on the ninety two carefully selected articles that allow this review to provide up-to-date information. Twenty nine papers were published within last 5 years, including 10 showed up in 2016-2017. Conclusion: The revision of the relevant literature showed that mycolic acids played a crucial role in host-pathogen interactions and thus might serve as a promising tool for differentiation of mycobacterial species and discovering novel tuberculocidal therapeutic strategies.

Background: Molecular lesions of the NRG1 gene were recently described as a new molecular feature of Invasive Mucinous Adenocarcinoma of the lung. The NRG1 chimeric ligand leads to aberrant activation of the ErbB2/ErbB3 signaling via PI3K–AKT and MAPK cellular cascades. This review aims to highlight the current knowledge about the ErbB network and the effect of NRG1 deregulation in lung cancer and their merger into the ErbB/PI3K-AKT axis modulation by current pharmacologic strategies. Methods: We performed a structured search of bibliographic databases for peer-reviewed literature to outline the state of the art with regard ErbB signaling deregulation and NRG1 function in lung cancer. The quality of retrieved papers was assessed using standard tools and one hundred thirty-five were included in the review. In many papers the molecular lesions affecting the ErbB receptors in lung cancer but also in other type of solid tumors were updated. Papers describing the physiological role of NRG1 in cells was also screened for the review preparation, as well as the paper reporting NRG1 fusions in lung cancer and their implication in aberrant ErbB pathway activation. Results and Conclusion: Overall, this review highpoints how the knowledge of new molecular mechanisms of ErbB pathway deregulation may help in gaining new insights into the molecular status of lung cancer patients and unveil a novel molecular markers of patients' stratification. Moreover, this ultimately led the selection of new compounds designed to inhibit the bound between Nrg1-ErbB3 as a good alternative way to block the ErbB intracellular signaling.

Background: Dementias and all related neurodegenerative diseases of the Central Nervous System (CNS) are a current issue arousing a great deal of interest in the international scientific community. This is due to the increasing number of patients suffering from these diseases. These pathologies represent a serious problem, not only concerning the quality of life of the patient, but in addition, the enormous economic efforts that society has to do for their treatment. There are currently a few strategies that are available in order to prevent the progression or to mitigate symptoms of the aforementioned diseases. This consideration is particularly true if we consider the specific pathology of Alzheimer's Disease (AD). Methods: We performed a literature search for peer-reviewed articles using different databases, such as PubMed or Scopus, and exploiting different keywords and different logical operators. Results: Ninety-eight papers were included in the review. Four papers give an overview of the background of the dementias all over the world. The remaining papers are focused on new possibilities of treatment with natural and semi-synthetic compounds for AD. Conclusion: The aim of this review is to give an overview of new and promising natural products and semi-synthetic compounds which could represent a source of “lead compounds” for the development of new potential drugs that could be a valid therapeutic strategy for the treatment of this pathology

Background: Immunomodulation is one of the significant therapeutic strategies. It includes both stimulation and suppression of the immune system by a variety of substances called immunomodulators, designed to regulate the immune response of the organism against infections of varying etiology. An example of such a substance is tuftsin (TKPA) 3 (Fig. (1)). In this paper were included tuftsin derivatives, which were described over the years, their together with biological activity and clinical potential. Methods: We reviewed a bibliographic database to gather all the important information about the tuftsin peptide. We have delineated the significant information on the activity of the tetrapeptide itself and its derivatives. Analogs were divided because of their anti-tumor, anti-inflammatory, antimicrobial and anti-viral activity. Results: This paper describes eighty-six documents. Thirty-two of them concern on activity of tuftsin in the human organism. The remaining fifty-four describe peptide analogues and their properties, including eleven papers about the tuftsin-based peptides contained in the vaccines, nine papers representing anticancer activity of the tuftsin derivatives, twenty-six about antiinflammatory compounds, and five papers describing the antitumor activity of the tuftsin analogs. Conclusion: The findings of this review confirm the importance of the tuftsin and their derivatives. Most of these substances showed anti-tumor, anti-inflammatory or antibacterial activities. A large amount of the compounds may find use in vaccines. Tuftsin can also be used to prepare fusion proteins in the treatment of cancer and as carriers of many biologically active substances.

Background: 4-Functionalized isoxazolin-5-ones (isoxazolones) have attracted much attentions as precursors of functionalized building blocks because the multiple functionalities. These structural features facilitate the construction of large compound libraries that is important for development of new functional materials. However, the systematic review article dealing with nitroisoxazolone has not been published although they exhibit different reactivity from other functionalized isoxazolones. This review describes the interesting behavior of the nitroisoxazolone motif and its application to the synthesis of polyfunctionalized compounds. Methods: Peer-reviewed research literatures describing the chemistry of nitroisoxazolones were collected, and each paper was appraised using standard criteria. inclusion/exclusion criteria. The papers were analyzed, and divided according to the reaction patterns. Results: This review consists of two parts. In the former part, the chemistry of pyridinium salt of nitroisoxazolone is described, and in the latter part, chemistry of methylnitroisoxazolone is introduced. Sixty-eight papers were included in this review. Twelve papers deal with pyridinium salt or its ring-opened product, cyano-aci-nitroacetate. Nine papers mention the chemistry of methylnitroisoxazolones and derived nitroenamines and nitrile oxide. With regard to each chemistry, reaction mechanism and reactivity are discussed with citing related literatures. Conclusion: The findings of this review confirm the importance of nitroisoxazolones in synthetic chemistry for polyfunctionalized compounds, which are not readily available by alternative methods. This review will provide useful information and synthetic tools for many chemists studying synthetic chemistry and medicinal chemistry.

Background: The design of multifunctional agents represents one of the most active research field in medicinal chemistry. In particular, tacrine, a well known Acetylcholinesterase inhibitor, is one of the most used starting point to develop multifunctional ligands and hundreds of papers report about these new agents. This is the third review of a series concerning tacrinebased multifunctional ligands; in particular, in the present, we will summarize and discuss the most intriguing examples of tacrine-based multifunctional agents published since 2013 until 2016. Methods: We analyzed the bibliographic databases for peer-reviewed publications concerning tacrine-based multifunctional agents possessing biological actions that go beyond the simple “cholinergic” blockage. These papers have been subdivided according to their biological activities. Since this is the third review of a series, we took into considerations only the papers appeared since 2013 until 2016. Results: In this review, we have analyzed more than 33 papers. All the reported compounds retain good inhibitory activity towards acetyl- and butyryl-cholinesterase. The other biological activities concern mostly inhibition of a) β-amyloid aggregation, b) β-secretase, c) monoamino oxidases, modulation of Τ and ROS and metal chelation. Conclusion: The analysis of the current literature reported in this review confirm the importance of tacrine as scaffold to develop multifunctional agents potentially usefull to contrast Alzheimer's disease. Furthermore, the compounds herein reported showed very intriguing biological activities that could be used as starting point to develop new compounds even more interesting and, hopefully, clinically usefull to contrast Alzheimer's Disease.

Background: The first reports of the natural enediyne anticancer antibiotics date back to the late 1980s; since then, a great deal of interest has been devoted to the chemistry, biology and potential medical applications of this family of compounds. The biological activity of enediynes is linked to the presence of a highly unsaturated hex-1-ene-1,5-diyne system. The thermally induced transformation of this unit into a benzene σ-σ diradical (the Bergman cycloaromatization) is the key step of the antitumor properties of such compounds: 1,4-diaryl radicals are able to abstract H-atoms from the deoxyribose backbone of DNA, thus leading to DNA strand cleavage and ultimately cell death. Methods: We undertook a structured search of bibliographic databases for peer-reviewed research literature using focused and high quality papers. Research efforts addressed at understanding and mimicking the various processes involved in the targeting, activation and DNA cleavage associated with these products are described. The potential of a great number of non natural enediynes in the treatment of many infectious diseases, apart their role in anticancer drugs, such as antibacterial activity, protein degradation activity, has been reported Results: Due to the interesting mode of action of this class of compounds, the unique molecular architecture of enediynes has been exploited towards the synthesis of many non natural compounds in order to study and enhance their biological properties. Seventy-six papers were included in this review. It is divided in paragraphs that include: Carbo- oxygen-nitrogen- and sulfur- enediynes, polymers and macrocycles. The synthetic approaches to the different classes of compounds are discussed in detail together with the biological implications of the synthesized compounds Conclusion: The review summarizes the most recent advances in the synthesis and reactivity of non natural enediynes by focusing the attention particularly to the biological properties of the most interesting members of the family of carbo- and hetero- enediynes. The findings of this review confirm the importance of non natural enediynes as potential drugs in the treatment of cancer and many infectious diseases.

Background: Diabetic nephropathy (DN) is an important diabetic microvascular complication, and it is becoming the leading cause of end-stage renal disease worldwide. Unfortunately, there are no effective therapies to treat established DN. Therefore, new therapeutic targets are urgently required. Accumulating studies indicate that mitochondrial dysfunction is central to the pathogenesis of DN, and therapies targeted mitochondria might effectively delay the progression of DN. Method: A structured search of previously research literature about mitochondrial structure and function, mitochondrial DNA, mitochondrial biogenesis, mitochondrial dynamics change, mitophagy, mitochondrial ROS, mitochondrial apoptosis and therapies targeted mitochondria has been performed in several databases. Result: 176 papers were included in this review, the results from these papers indicated that mitochondrial dysfunction is a pivotal issue for the development of DN, such as elevated oxidative stress induced by disorders of the mitochondrial respiratory chain complex and mitochondrial dynamic disorders, mutation of mitochondrial DNA, mitochondrial abnormal biogenesis, mitochondrial excessive fission, mitochondrial ROS overproduction. In addition, several therapeutic agents targeting the mitochondria (e.g mitochondrial ROS modulators, mitochondrial fragmentation inhibitors and mitochondrial biogenesis activators) have shown perfect therapeutic effect and security for DN. Conclusion: The finding of this review has further confirmed the vital role of mitochondrial dysfunction in the progression of DN, management strategies for recovering the normal mitochondrial function will offer potential novel therapeutic targets for DN.

Background: The metabolic syndrome (MetS) is a cluster of risk factors for the development of cardiovascular diseases (CVD) and type 2 diabetes (T2DM). According to several meta-analyses, it has been shown that the cardiovascular (CV) risk conferred by the MetS is higher in women in comparison with men. There are many possible reasons to explain a higher CV risk in women with MetS: the most important differences can be attributed to distribution of central adiposity, lipid profile and hormones, but also differences in platelet biology and biochemistry play an important role. Methods: In this article we performed a research using PubMed database reviewing the evidence in literature (in particular clinical trials and meta-analyses) or lack of evidence/ biased information regarding the distribution by gender of MetS components and associated CV risk and we intended to provide a consequent gender perspective to the treatment of MetS and CV risk. Results: Twenty-three papers were evaluated searching for sex differences in the prevalence of MetS and CV risk. We also identified fifty-six papers dealing with sex differences in adiposity, insulin resistance and hormonal regulation. In terms of gender-specific expression of MetS in chronic disease we analyzed thirty-one papers focusing the attention on non-alcoholic fatty liver disease, polycystic ovarian syndrome, gestational diabetes mellitus, rheumatoid arthritis and HIV infection. We also evaluated twenty papers focusing on gender differences in platelet biology/reactivity and thirty-three papers on the gender approach in the treatment of MetS. The CV risk conferred by MetS segregates differently according to gender; differences between sexes may depend on the different representation of MetS components, gender-specific genetic, acquired metabolic and hormonal milieu and finally on a differential interaction between known risk factors and genderspecific properties, resulting in different degrees of pathophysiological events eventually leading to atherothrombosis. Regarding a potential sex-related therapeutic approach, even if gender-related differences exist in the pharmacokinetics of drugs for differences in body composition, plasma protein binding, metabolizing enzymes and difference in excretion characteristics, we have to acknowledge that women are under-represented in clinical trials, thus preventing from adequately challenging the efficacy and safety of drugs in this gender. Conclusion: While ncreasing knowledge exists regarding pathophysiological differences between genders in the prevalence of MetS components as well as in the associated cardiometabolic risk, underrepresentation of women in clinical trials and underutilization of guideline therapy, for instance in women with ischemic heart disease, largely flaw the interpretation of epidemiological and clinical evidence. Efforts should be undertaken to fight the so-called “Yentl syndrome” and to promote gender-specific drug trials, or at least studies where subgroup analyses by gender are pre-specified.

Background: Aging is a phenomenon in which the functions, adaptability and resistance of an organism decrease over time. With the global population aging at an accelerating pace, delaying the negative aspects of aging is vital for advancing the human life span and quality of life. The aging of multiple organs can lead to many diseases, and the cardiovascular system is no exception. Indeed, one of the primary risk factors for cardiovascular diseases is aging because of altered cardiovascular metabolism resulting in metabolic disorders and inflammation. Methods: We attempted an organized search of bibliographic databases for peer-reviewed research papers by searching featured reviews using inclusion/exclusion criteria. The collected papers were assessed by standard tools for quality control. Results: Forty-six papers were admitted to the review, and most papers featured recent research results (44) and reviewed the research field (8). We discuss these papers along with the recent progress of our work. In this review, we examine the relationship of oxidative stress with aging and the FoxO proteins, which are essential anti-aging factors in the cardiovascular system. Conclusion: The observations of this review suggest that anti-aging signaling mediated by FoxO proteins is important for understanding cardiovascular aging and the design of medicinal approaches.